Overexpression of tumor suppressor TSLC1 by a survivin-regulated oncolytic adenovirus significantly inhibits hepatocellular carcinoma growth.

PURPOSE: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Oncolytic viruses represent a promising therapeutic agent or vehicle to human cancers due to their ability of selectively lysing cancer cells but not in normal cells. TSLC1, a novel tumor suppressor gene, was loss in many human cancers including HCC, not in normal cells. The current study is focused on the antitumor effect of TSLC1-armed survivin-regulated oncolytic adenovirus for HCC and to explore their molecular mechanism.

METHODS: The expression of tumor suppressor TSLC1 and survivin was detected by quantitative PCR. The recombinant virus Ad.SP-E1A-E1B((Δ55))-TSLC1 (brief name as SD55-TSLC1) was constructed by inserting TSLC1 gene into the dual-regulated oncolytic adenovirus vector Ad.SP-E1A-E1B((Δ55)). Then, we performed the antitumor experiments of SD55-TSLC1 in vitro and in nude mice xenografted with Huh7 liver cancer.

RESULTS: The expression of TSLC1 was lower in HCC cells than in normal cells, which implied TSLC1 is a tumor suppressor of liver cancer. Survivin expression is higher in detected HCC cells than in normal cells. The SD55-TSLC1 exhibited an excellent antitumor effect on HCC cell growth in vitro but does no or little damage to normal liver cells. Animal experiment further confirmed that SD55-TSLC1 achieved significant inhibition of Huh7 liver cancer xenografted growth. Furthermore, the mechanism of antitumor efficacy by SD55-TSLC1 was elucidated to be due to the activation of caspase apoptotic pathway including the inducement of caspase-3, caspase-8, and poly (ADP-ribose) polymerase cleavage. This is the first report of TSLC1 by oncolytic adenovirus with an excellent antitumor effect to liver cancer growth.

CONCLUSION: These data suggest that an oncolytic adenovirus expressing TSLC1 is effective and support that SD55-TSLC1 may be a potent antitumoral agent for future clinical trials of liver cancer.